Andy Mackinnon

Abstract 552: Immuno-oncology agent CB-1158 is a potent and selective arginase inhibitor and causes an immune-mediated anti-tumor response

L-arginine is a critical metabolite for T-cell receptor signaling and subsequent T-cell proliferation, and depletion of arginine arrests T-cell growth. In the tumor microenvironment, infiltrating myeloid-derived suppressor cells (MDSCs), macrophages, and neutrophils produce arginase, which depletes local arginine concentrations and dampens T cell-mediated immune surveillance. Pharmacological inhibition of arginase is expected to restore arginine levels and allow T-cells to proliferate, thereby leading to an immune-mediated anti-tumor response. CB-1158 is a potent inhibitor of human arginase (IC50 = 98 nM). In culture, human granulocytes release arginase and deplete media arginine to levels that inhibit T-cell proliferation. In a co-culture system of human granulocytes and T-cells, CB-1158 potently blocks granulocyte-derived arginase activity, maintains extracellular arginine levels, and restores proliferation of T-cells. CB-1158 has high oral bioavailability in rodents and is very well tolerated. BID oral dosing of CB-1158 leads to dose-dependent pharmacodynamic increases in plasma and tumor arginine levels resulting in single agent anti-tumor efficacy in mouse syngeneic tumor models including Lewis Lung carcinoma (LLC) and Madison 109. The anti-tumor effects of CB-1158 are consistent with promoting a proinflammatory tumor microenvironment. Following CB-1158 treatment, multiple Th1 T-cell, NK-cell, and M1 macrophage-associated chemokines, cytokines, and activation markers are elevated in the LLC tumor microenvironment. The anti-tumor efficacy of CB-1158 requires an intact tumor microenvironment since CB-1158 has no effect on LLC cell growth in vitro. Furthermore, CB-1158 treatment of immunocompromised C57/SCID mice bearing LLC tumors has no anti-tumor effect, supporting an immune-mediated anti-tumor mechanism. Immunosuppression in the tumor microenvironment can occur via multiple mechanisms, including arginine depletion, and our data support the combination of checkpoint inhibitors and arginase inhibition by CB-1158. In mice bearing LLC tumors, CB-1158 in combination with checkpoint inhibitors reduced tumor growth, increased the number of tumor infiltrating CD8+ T-cells, and increased the level of Th1/NK/M1-associated chemokines, cytokines, and activation markers in the tumor microenvironment. In mice bearing 4T1 tumors, a tumor type that is highly refractory to checkpoint inhibition, the combination of CB-1158 with anti-PD-1 and anti-CTLA-4 reduces tumor growth and lung metastases. These results support the development of CB-1158, a first-in-class arginase inhibitor, as a novel immuno-oncology agent targeting the immunosuppressive effects of tumor-infiltrating myeloid cells. Citation Format: Melissa Works, Mark Bennett, Jason Chen, Ethan Emberley, Tony Huang, Julie Janes, Weiqun Li, Andy Mackinnon, Gisele Marguier, Silinda Neou, Alison Pan, Francesco Parlati, Mirna Rodriguez, Susanne Steggerda, Tracy Wang, Jing Zhang, Winter Zhang, Matthew Gross. Immuno-oncology agent CB-1158 is a potent and selective arginase inhibitor and causes an immune-mediated anti-tumor response. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 552.

Abstract 1416: CB-839, a novel potent and selective glutaminase inhibitor, has broad antiproliferative activity in cell lines derived from both solid tumors and hematological malignancies

Many tumor cells utilize altered metabolic pathways to meet the bioenergetic and biosynthetic demands of rapid and sustained growth. One of the key nutrients that fuels tumor growth is the amino acid glutamine. It has long been recognized that the growth and survival of many tumor cell lines in vitro is dependent on extracellular glutamine. A critical step in the utilization of glutamine is its conversion to glutamate by the mitochondrial enzyme glutaminase. Glutamate and glutamate-derived metabolites in turn support a number of crucial cellular pathways including the citric acid cycle, redox balance and amino acid synthesis. CB-839 is a novel and selective inhibitor of glutaminase that has antitumor activity in preclinical models of triple negative breast cancer (TNBC), a tumor type that is particularly dependent on glutamine. Across a panel of breast cancer cell lines, the activity of CB-839 correlates with high expression of glutaminase, specifically the GAC splice variant but not the KGA splice variant, and low expression of glutamine synthetase (GLUL), an enzyme that converts glutamate to glutamine. This expression pattern is found in primary TNBC tumors suggesting a reliance on exogenous glutamine and glutaminase activity in vivo. To determine if other tumor types have a similar expression pattern, we undertook a systematic evaluation of GAC, KGA and GLUL expression across a diverse set of primary tumors using a normalized microarray dataset allowing comparison across a range of tumor and normal tissue samples. Elevated GAC and decreased GLUL expression relative to other tumor types or corresponding normal tissue was identified in a number of tumor types including non-small cell lung cancer, multiple myeloma, and non-Hodgkin9s lymphoma. To explore whether this expression pattern predicts a reliance on glutamine and glutaminase, we tested the glutamine dependence and the activity of CB-839 on a panel of 72 cell lines representing 5 tumor types indicated by the primary tumor expression analysis. Across this cell line panel, the majority were dependent on glutamine showing either cell death, growth arrest or slowed growth after glutamine withdrawal. Similarly, CB-839 had antiproliferative activity in the majority of cell lines with IC50s in the range of 10-300 nM. Importantly, there was a strong correlation between glutamine dependence and response to 1 µM CB-839 as measured by relative cell growth or death (correlation coefficient 0.72, p Citation Format: Francesco Parlati, Susan D. Demo, Matthew I. Gross, Julie R. Janes, Evan R. Lewis, Andy L. MacKinnon, Mirna L.M. Rodriguez, Peter J. Shwonek, Taotao Wang, Jinfu Yang, Dong Zhang, Frances Zhao, Mark K. Bennett. CB-839, a novel potent and selective glutaminase inhibitor, has broad antiproliferative activity in cell lines derived from both solid tumors and hematological malignancies. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1416. doi:10.1158/1538-7445.AM2014-1416

Abstract B045: Arginase inhibitor CB-1158 elicits immune-mediated antitumor responses as a single agent and in combination with other immunotherapies

Myeloid derived suppressor cells (MDSCs) and polymorphonuclear cells (PMNs) are mediators of tumor immune evasion, however there are no approved clinical agents that directly antagonize the immunosuppressive activity of these cells. One of the mechanisms by which MDSCs and PMNs suppress anti-tumor immunity is expression of the enzyme arginase, which reduces L-arginine levels rendering T-cells and natural killer (NK)-cells unable to proliferate and mount an effective anti-tumor response. As a rationale to pursue arginase inhibition as a potential therapeutic strategy, we investigated the prevalence of arginase in tumors and peripheral blood from patients with various types of cancer. Our results confirm reports that multiple tumor types have arginase-expressing PMN infiltrates and that cancer patients have higher levels of plasma arginase and lower levels of plasma arginine compared to healthy volunteers. We also confirmed that in vitro-activated primary human T-cells and NK-cells require arginine to proliferate, secrete pro-inflammatory cytokines, and express the intracellular signaling molecule CD3ζ and cell surface activation marker PD-1. We developed CB-1158 to be a potent, selective, and orally-bioavailable small molecule inhibitor of arginase. CB-1158 potently inhibits recombinant human arginase 1 (IC 50 = 98 nM), recombinant human arginase 2 (IC 50 = 249 nM), and endogenous arginase from human neutrophils (IC 50 = 160 nM). In a co-culture system, neutrophils strongly suppressed T-cell proliferation. The addition of CB-1158 blocked arginase activity, maintained arginine levels in the media, and allowed T-cells to proliferate in the presence of suppressive myeloid cells, suggesting that arginase is a major mechanism of myeloid cell suppression of lymphocyte proliferation and that CB-1158 can reverse the suppression. To extend these findings to MDSCs, we isolated peripheral monocytic MDSCs (M-MDSCs) or granulocytic MDSCs (G-MDSCs) from cancer patients and found that G-MDSCs expressed higher levels of arginase, depleted more arginine from cell-culture media, and were more suppressive to T-cell proliferation compared to M-MDSCs. Incubation of G-MDSCs with CB-1158 resulted in media arginine levels that could support T-cell proliferation. CB-1158 has high oral bioavailability in mice and rats. Twice-daily oral dosing of CB-1158 produced dose-dependent pharmacodynamic increases in plasma and tumor arginine levels and resulted in single-agent anti-tumor efficacy in the murine syngeneic tumor models Lewis Lung carcinoma (LLC1), Madison-109 lung carcinoma, and B16F10 melanoma. Antibody-mediated depletion of either CD8 + T-cells or NK-cells partially abrogated the anti-tumor effect of CB-1158 in the LLC1 and B16F10 models indicating that the mechanism of action of CB-1158 is immune cell-mediated through the actions of both T-cells and NK cells. Corroborating the immune-mediated anti-tumor efficacy in CB-1158-treated LLC1 tumors, following dosing with CB-1158 we observed increases in tumor infiltrating CD8 + T-cells; increased levels of tumor Th1 T-cell cytokines; increased expression of T-cell and NK-cell activation markers; and increased interferon-inducible genes. Based on the novel mechanism of action of CB-1158, there is potential for enhanced therapeutic benefit by combining CB-1158 with other immunotherapies. We observed improved anti-tumor activity by combining CB-1158 with either epacadostat or anti-PD-L1 in the B16F10 model, with low dose ionizing radiation in the Madison-109 model, and with gemcitabine in the LLC1 model. These results support the development of CB-1158, a first-in-class arginase inhibitor, as a novel immuno-oncology agent targeting the immunosuppressive effects of tumor-infiltrating myeloid cells. Citation Format: Susanne M. Steggerda, Mark Bennett, Jason Chen, Ethan Emberley, Matthew Gross, Tony Huang, Weiqun Li, Andy MacKinnon, Amani Makkouk, Gisele Marguier, Silinda Neou, Alison Pan, Tracy Wang, Melissa Works, Jing Zhang, Winter Zhang, Francesco Parlati. Arginase inhibitor CB-1158 elicits immune-mediated antitumor responses as a single agent and in combination with other immunotherapies [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B045.

Abstract 2329: Glutaminase inhibition with CB-839 enhances anti-tumor activity of PD-1 and PD-L1 antibodies by overcoming a metabolic checkpoint blocking T cell activation

Recent studies have highlighted the importance of the tumor metabolic environment for controlling immune activation. T-cells activated through the TCR/CD28 receptor switch to a highly glycolytic metabolism and increase their requirement for glucose and glutamine. Consequently, limited availability of glucose or glutamine can block T-cell activation and proliferation. Likewise, immune checkpoints proteins, PD-1 and CTLA-4, suppress T cell metabolism by inhibiting glycolysis, glutamine uptake and glutaminolysis (Patsoukis et al Nat Comm. 2015). Chang et al (Cell. 2015) recently demonstrated that glucose consumption by tumors restricts glucose availability and blocks activation of T cells, and that treatment with CTLA-4, PD-1, or PD-L1 antibodies can re-activate T cell glycolysis. CB-839 is a glutaminase inhibitor currently in Phase 1 trials in patients with solid and hematological malignancies. CB-839 blocks glutamine consumption in tumors and causes a significant elevation of tumor glutamine levels. Therefore, we hypothesized that CB-839 might enhance the activity of immune checkpoint inhibitors via metabolic modulation of the tumor microenvironment. We first confirmed that T- cell proliferation is dependent on glutamine but is only minimally inhibited by CB-839. In the absence of glutamine, splenic mouse T cells stimulated with anti-CD3/CD28 had reduced glucose consumption and did not proliferate. In contrast, CB-839 treatment did not mimic the effects of glutamine withdrawal on T-cells. CB-839 had no effect on glucose consumption by activated T-cells and only a minimal effect on proliferation. We also confirmed in the OVA vaccinia model that CB-839 had minimal effects on CD4 and CD8 T-cell proliferation in vivo, while the non-specific glutamine inhibitor DON caused a dramatic reduction in the number of CD4 and CD8 T-cells. To determine if CB-839 could enhance the anti-tumor efficacy of immune checkpoint inhibitors, we treated mice bearing syngeneic CT26 colon carcinoma tumors with anti PD-1 or anti PD-L1 alone or in combination with CB-839. The addition of CB-839 to either anti PD-1 or anti PD-L1 treatment enhanced anti-tumor activity, augmenting tumor regression and promoting survival. Depletion of CD8+ T-cells from CT26 tumors reversed the anti-tumor effects of PD-L1 and CB-839, demonstrating that the combination targets CD8+ T-cells in the immune microenvironment. These data are the first demonstration that modulation of glutamine metabolism in tumors can enhance the activity of checkpoint inhibitors and provide a rationale for combining CB-839 with immune checkpoint inhibitors in the clinic. Overall, these data highlight a new therapeutic approach to treating cancer by targeting tumor metabolism as a means of enhancing the efficacy of immunotherapy. Citation Format: Matt Gross, Jason Chen, Judd Englert, Julie Janes, Robert Leone, Andy MacKinnon, Francesco Parlati, Mirna Rodriquez, Peter Shwonek, Jonathan Powell. Glutaminase inhibition with CB-839 enhances anti-tumor activity of PD-1 and PD-L1 antibodies by overcoming a metabolic checkpoint blocking T cell activation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2329.

Abstract A195: CB-1158 inhibits the immuno-oncology target arginase and causes an immune mediated anti-tumor response

The role of myeloid derived suppressor cells (MDSCs) has become increasingly recognized as an important mechanism of tumor immune evasion. However, to date there are no effective means to antagonize the immunosuppressive activity of these cells in patients. MDSCs suppress cytotoxic T-cells and Natural Killer cells through the secretion of the enzyme arginase which depletes local arginine concentrations. The depletion of arginine in the tumor microenvironment renders cytotoxic T-cells unable to proliferate and therefore unable to effectively mount an anti-tumor attack. Similarly, M2 macrophages and polymorphonuclear cells (PMNs) express high levels of arginase and may contribute to the local suppression of immune responses. Restoration of arginine levels in the tumor microenvironment via arginase inhibition would be expected to allow T-cell activation and proliferation to occur and result in T-cell mediated anti-tumor responses. We have developed novel, potent, and specific inhibitors of arginase. Our clinical candidate CB-1158 has an IC 50 of less than 100 nM in a recombinant human arginase assay. As expected, inhibition of arginase in cell culture does not have a direct anti-proliferative effect on any cell type tested. However, in Peripheral Blood Mononuclear Cells (PBMCs) from a patient with renal cell carcinoma containing both suppressive MDSCs and cytotoxic T-cells, the addition of an arginase inhibitor to the MDSC/T-cell co-culture resulted in a dose-dependent increase in T-cell proliferation relative to vehicle controls. CB-1158 has high oral bioavailability in mice and rats. In mice bearing Lewis Lung Carcinoma (LLC) syngeneic tumors, treatment with CB-1158 results in a 3-4 fold increase in tumor arginine levels with a clear pharmacokinetic/pharmacodynamic relationship. The pharmacodynamic effect of arginase inhibition in tumors was sustained throughout a 24-hour period using a twice-daily oral dosing schedule and has been observed in multiple syngeneic models. Moreover, systemic plasma arginine levels are significantly increased in mice following dosing with CB-1158. Importantly, oral dosing with CB-1158 results in single agent anti-tumor efficacy in the LLC model in C57.Bl/6 mice. In contrast, treatment of immunocompromised C57/scid mice bearing LLC tumors with CB-1158 had no effect on tumor growth. This finding is consistent with the observed anti-tumor efficacy in immune competent mice being mediated through an immune mechanism. Evaluation of tumors treated with arginase inhibitors revealed an increase in CD3+ T-cell infiltrates further supporting an immune-based mechanism of action. CB-1158 has been very well tolerated in rodents with no impact on body weights or serum chemistry enzymes following multi-week dosing schedules. CB-1158 is a first-in-class arginase inhibitor that targets the immunosuppressive effects of myeloid cells in the tumor microenvironment and is currently in development as a novel immuno-oncology strategy. Based on this novel mechanism of action there is also a potential for enhanced therapeutic benefit by combining CB-1158 with other immune checkpoint inhibitors. Citation Format: Matthew Gross, Jason Chen, Ethan Emberley, Julie Janes, Weiqun Li, Andy Mackinnon, Alison Pan, Francesco Parlati, Mirna Rodriguez, Susanne Steggerda, Tracy Wang, Melissa Works, Jing Zhang, Winter Zhang, Mark Bennett. CB-1158 inhibits the immuno-oncology target arginase and causes an immune mediated anti-tumor response. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A195.

Abstract P1-08-07: A novel pharmacodynamic assay to measure glutaminase inhibition following oral administration of CB-839 in triple negative breast cancer biopsies

Triple negative breast cancer (TNBC) cell lines are highly dependent on glutamine (Gln) for growth and survival. A critical step in Gln utilization is its conversation to glutamate (Glu) by the mitochondrial enzyme glutaminase (GLS). CB-839 is a potent inhibitor of GLS that has anti-proliferative activity in TNBC cell lines and antitumor activity in TNBC xenograft models (Gross et al., Mol. Cancer Ther. 13:890). Across a panel of breast cancer cell lines derived from both receptor positive and TNBC tumors, sensitivity to CB-839 was associated with (i) elevated GLS expression, (ii) elevated GLS activity, and (iii) the TNBC subtype. Importantly, many of the determinants of CB-839 sensitivity in cell lines are also present in primary tumor samples, including high mRNA and protein expression of GLS and a high Glu to Gln ratio in TNBC tumors as compared to receptor positive tumors. These observations motivate the Phase 1 clinical study of CB-839 in TNBC patients. To aid in the selection of a recommended Phase 2 dose, we sought to develop a pharmacodynamic (PD) assay to directly measure the GLS activity in breast tumor lysates in order to determine the extent of GLS inhibition in tumor biopsies from CB-839 treated patients. To develop a robust PD assay, we first identified conditions that maintain the GLS:CB-839 inhibitory complex during preparation of lysates from CB-839 treated samples. High concentrations of KCl (150 mM) and low concentrations of K-phosphate (15 mM) in the lysis buffer, as well as maintaining the lysate at a low temperature stabilized the inhibited complex. Following gel filtration of the lysate to remove unbound CB-839 and exchange the buffer, GLS activity was immediately measured with a coupled enzyme assay. The GLS activity measured at this step reflects the residual activity present in a sample that was exposed to CB-839. To quantify the amount of total GLS present in the sample, we incubated the same lysate for 3 hours at room temperature under conditions of low KCl and high phosphate to allow the the GLS:CB-839 complex to fully dissociate prior to measuring activity. This assay format allows quantitation of the % GLS inhibition from a single tumor lysate sample and eliminates the requirement for multiple biopsies as well as any assay variability due to tumor heterogeneity. We utilized this tumor PD assay to determine the plasma drug levels required for maximal tumor GLS inhibition in a preclinical TNBC model. Mice bearing HCC1806 TNBC tumors were first treated with a range of CB-839 doses. Four hours after oral administration, a 10 mg/kg dose of CB-839 resulted in >90% inhibition of tumor GLS. CB-839 plasma concentrations of 100 nM corresponded to 50% inhibition of tumor GLS, while maximal inhibition occurred at plasma concentrations ≥300 nM. In xenograft studies, maximal anti-tumor efficacy was achieved with BID dosing at 200 mg/kg, a dose and schedule that resulted in trough plasma levels of CB-839 of ≥300 nM and sustained GLS inhibition in tumors. As part of an ongoing Phase 1 trial, this assay will be utilized to monitor tumor PD responses in TNBC patients undergoing treatment. Citation Format: Andy MacKinnon, Mark Bennett, Ethan Emberley, Mathew Gross, Julie Janes, Evan Lewis, Alison Pan, Mirna Rodriguez, Peter Shwonek, Taotao Wang, Jinfu Yang, Frances Zhao, Francesco Parlati. A novel pharmacodynamic assay to measure glutaminase inhibition following oral administration of CB-839 in triple negative breast cancer biopsies [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-08-07.

Abstract 966: Novel pharmacodynamic assays to measure glutaminase inhibition following oral administration of CB-839

Glutaminase is a mitochondrial enzyme that plays a crucial role in tumor growth and survival. Glutaminase converts glutamine (Gln) to glutamate (Glu) fueling multiple downstream metabolic pathways required for cellular proliferation. CB-839 is a novel, selective and potent inhibitor of glutaminase that displays antitumor activity in preclinical models of several hematologic and solid tumor types. Treatment of tumor cell lines in vitro with CB-839 caused dose-dependent decreases in Glu and increases in Gln with a potency similar to the IC50 of CB-839 on recombinant glutaminase and the EC50 of CB-839 in cellular proliferation assays. Oral administration of CB-839 to mice bearing human xenograft tumors resulted in similar changes in Glu and Gln levels in the tumor. To determine if these pharmacodynamics effects of CB-839 directly correlated with inhibition of glutaminase, we developed an assay to measure glutaminase activity in tumors. Since CB-839 is a reversible inhibitor, we first developed conditions that maintain the enzyme-inhibitor complex during preparation of tumor lysates. High concentrations of KCl (150 mM) and low concentrations of K-phosphate (15 mM) in the lysis buffer, as well as maintaining the lysate at a low temperature promoted stability of the inhibited complex. Following gel filtration to remove unbound CB-839 and exchange the buffer, glutaminase activity was measured with a coupled enzyme assay. This assay was used to study the dose-dependence of glutaminase inhibition in tumors. Four hours after oral administration, a 10 mg/kg dose of CB-839 resulted in >90% inhibition of tumor glutaminase and was associated with near maximal changes in tumor Gln and Glu. Moreover, CB-839 plasma concentrations of 100 nM corresponded to 50% inhibition of tumor glutaminase, while maximal inhibition occurred at plasma concentrations ≥300 nM. In xenograft studies, maximal anti-tumor efficacy was achieved with BID dosing at 200 mg/kg. This dose and schedule allowed for sustained plasma levels of CB-839 of ≥300 nM, and corresponded to sustained glutaminase inhibition in tumors. In an effort to develop a surrogate marker for inhibition of tumor glutaminase, we adapted the assay to measure glutaminase inhibition in platelets. Ex vivo treatment of human whole blood with CB-839 resulted in dose-dependent suppression of platelet glutaminase activity with an IC50 of 25 nM and >85% inhibition at concentrations at or above 300 nM. Furthermore, glutaminase activity in platelets isolated from mice treated with CB-839 showed dose-dependent inhibition that correlated with inhibition of tumor glutaminase. Thus, platelet glutaminase activity may represent a surrogate for monitoring inhibition of glutaminase in human tumors. These assays will be applied to the clinical study of CB-839 to monitor pharmacodynamic responses and to ensure maximal inhibition of glutaminase in patients undergoing therapy. Citation Format: Andy L. MacKinnon, Mark K. Bennett, Matthew I. Gross, Julie R. Janes, Evan R. Lewis, Mirna L.M. Rodriguez, Peter J. Shwonek, Wang Taotao, Jinfu Yang, Frances Zhao, Francesco Parlati. Novel pharmacodynamic assays to measure glutaminase inhibition following oral administration of CB-839. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 966. doi:10.1158/1538-7445.AM2014-966

Abstract P2-09-03: Antitumor activity of the glutaminase inhibitor, CB-839, in triple-negative breast cancer

Glutamine (Gln) serves as an important source of energy and building blocks for many tumor cells. The first step in Gln utilization is its conversion to glutamate (Glu) by the mitochondrial enzyme glutaminase. CB-839 is a potent, selective, and orally bioavailable inhibitor of both splice variants of glutaminase (KGA and GAC). CB-839 inhibits recombinant GAC with an IC50 of 25) that included a mixture of TNBC and ER/Her2-positive subtypes. The TNBC subtype displayed the greatest sensitivity to CB-839 treatment (IC50s ranging from 5-100 nM) and this sensitivity was correlated with: i) dependence on extracellular Gln for growth (r = 0.83, p Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-09-03.